Natural Product Reports
Recent advances in the use of vibrational chiroptical spectroscopic methods for stereochemical characterization of natural products
Journal: Natural Product Reports
Manuscript ID: NP-REV-02-2015-000027.R1
Article Type: Review Article
Date Submitted by the Author: 22-May-2015
Complete List of Authors: Bolzani, Vanderlan; São Paulo State University (UNESP), Institute of Chemistry Batista Junior, Joao Marcos; Federal University of Sao Carlos - UFSCar, Chemistry Blanch, Ewan; RMIT University, School of Applied Sciences
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Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx ARTICLE TYPE
Recent advances in the use of vibrational chiroptical spectroscopic methods for stereochemical characterization of natural products
João Marcos Batista Jr.,* a Ewan W. Blanch b and Vanderlan da Silva Bolzani*c
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5 DOI: 10.1039/b000000x
This review covers conformational and configurational assignments in natural product molecules using chiroptical spectroscopy reported over the last 15 years. Special attention is given to vibrational optical activity methods associated with quantum mechanical calculations. Covering: 2000 to 2014
ROA, on the other hand, results from a small difference in the Introduction intensity of vibrational Raman scattering from chiral molecules when using right and left circularly polarized incident light 10 Chirality is omnipresent in nature manifesting itself in all 1 50 (ICP ROA). It can be equivalently measured as the difference in material objects ranging from fundamental particles to galaxies. intensity of a small circularly polarized component in the When it comes to natural product chemistry, molecular chirality, scattered light by using incident light of fixed nonelliptical that is, the chiral three dimensional arrangement of atoms in a polarization (SCP ROA). given molecule, is of paramount importance to the understanding 2 OR, ORD, ECD, VCD, and ROA, which are all inherently 15 of biosynthesis, functions and biological activities. However, 55 sensitive to chirality, are nondestructive methods that can be characterizing such arrangements in the absolute sense is not a measured directly in solution, without the need of crystallization trivial task. Enantiomers share, in an achiral environment, or the use of chiral auxiliaries. Additionally, due to their basically the same physical and chemical properties that make sensitivity to molecular conformations, not only is absolute them indistinguishable in many aspects. One way of getting stereochemistry determination feasible but also conformational 20 around this problem is to take advantage of the diastereomeric 60 analysis in solution. Nevertheless, the interpretation of chiroptical discrimination provided by chiroptical methods. 3 data in order to obtain molecular structure information is not Although the term “chiroptical” (Chiral + Optical) may not be straightforward. Although the so called ECD “exciton chirality” readily recognizable to all natural product chemists, this concept method (ECM) 6 has been successfully used for many years to is commonly present in their everyday lives. Optical rotation determine the absolute configuration of suitable molecules, only 25 (OR, polarimetry), one of the oldest chiroptical methods 65 recently, due to the development of reliable ab initio calculations available, is widely used in teaching, analytic, synthetic and for predicting theoretical spectra, the use of chiroptical methods natural product laboratories, mainly to determine enantiomeric 4 for configurational analysis of chiral molecules faced a purity. Other examples of chiroptical methods include optical 7 renaissance. rotatory dispersion (ORD), electronic circular dichroism (ECD), This renewed interest in chiroptical spectroscopy methods 30 and vibrational optical activity (VOA) methods, represented by 70 involved not only VOA techniques. The development of the vibrational circular dichroism (VCD) and Raman optical activity accurate theoretical calculations mentioned above also greatly (ROA). The latter two will be the focus of the present review expanded the applicability of OR/ORD and ECD for structural article. characterization of natural products, with a great number of All chiroptical methods arise from the differential interaction reports published every year. Interestingly, these calculations 35 of a chiral non racemic molecule with left and right circularly 5 75 have recently revealed the first apparent exception of ECM for a polarized light beams, which are chiral entities with one being simple biaryl system. 8 Although not the focus of this review the mirror image of the other. OR and ORD (variation of OR with article, excellent references on the use of OR/ORD and ECD wavelength) are based on different indices of refraction for left techniques for synthetic and natural organic molecules can be and right circularly polarized light in a chiral (optically active) 5,9 27 found here. 40 medium, known as circular birefringence. As light traverses a 80 Compared to the other chiroptical methods, VCD and ROA chiral medium, the circularly polarized electromagnetic field present some advantages, since they can be measured for virtually components slow to a different extent and the plane of any molecule without the requirement of either UV Vis polarization is rotated with respect to the original case. Circular chromophores for ECD, derivatizations, or simulations of dichroism methods originate from the differential absorption by a excited state wavefunctions. In addition, as these two 45 chiral molecule of left versus right circularly polarized radiation 85 spectroscopic methods represent global molecular properties, all during an electronic (ECD) or vibrational transition (VCD). degrees of freedom (3N 6, where N is the number of atoms) of a
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molecule can be investigated, at least in theory. Nevertheless, at consists of extracting dipole and rotational strengths from the same time, it becomes more difficult to extract stereochemical experimental data and plotting it against the calculated values. information from VOA spectra, which increases the dependence 60 This method offers the possibility of calculating statistical on the accuracy of the calculations. VCD and ROA also require measures, such as the correlation coefficient R 2.30 A second 44 5 larger amounts of sample (~ 0.01 0.1M) and longer acquisition method called SimIR/VCD uses computationally optimized times (~ 1 12 h) than do OR/ORD and ECD. frequency scaling and shifting to match calculated and observed Despite the advantages described above, an early review article spectra. A third method is the confidence level algorithm 45 that 28 on chiroptical methods published by Allenmark in 2000, 65 provides a direct quantitative comparison of the experimental presented only a single example on the use of VCD for natural spectrum with the calculated spectra for both enantiomers as a 10 products (the Scolytidae insect pheromone frontalin). Fortunately, measure of the degree of agreement and hence level of this scenario has been changing rapidly and a number of review confidence. The most recent method is based on the similarity of articles and book chapters have already been published dealing dissymmetry factor spectra placing emphasis on robust regions 46 with the use of VOA to natural product chemistry, although 70 both in the experimental and calculated spectra. focused mainly on VCD. 5,25,29 36 Recently, there have also been some attempts to interpret VCD 15 The present review will report approximately 190 molecules data without the aid of theoretical calculations, which resulted in whose stereochemical properties have been studied using VOA the development of the exciton chirality method for VCD. 47 methods, including VCD and ROA, over the last fifteen years. Briefly, this methodology is based on the coupling of two We hope this comprehensive review will demonstrate the 75 infrared chromophores (e.g. carbonyl groups) that yields a strong evolution of the applications of VOA to natural product VCD couplet whose sign reflects the absolute configuration of 20 chemistry, and help spread the word about the potential of these the molecule. methods to solve stereochemical problems of chiral natural However, it is important to emphasize that, even when DFT molecules. calculations are employed to generate theoretical spectra, the 80 assignment of absolute configurations may be inaccurate. This VOA techniques may be caused by errors in the equilibrium geometries and conformational populations as mentioned before, by density VCD and ROA were first measured in the early to mid 1970s, 37 39 functional and/or basis set errors, and finally by solvent effects. 25 and, ever since then, VOA has undergone tremendous Density functional and basis set errors are expected to develop in evolution that culminated in the availability of user friendly 85 any quantum mechanical calculation because it is based on commercial instrumentation 40 and software packages 41 for approximations of atomic wave functions, the accuracy of such reliable spectral measurement and quantum mechanical predictions being sensitive to the choice of the functional (either calculations of theoretical spectra. The determination of the pure or hybrid), and directly proportional to the size of the basis 30 absolute configuration and conformations of chiral small set used. Solvent effects may be considered one of the most molecules using VOA consists of comparing the sign and 90 important sources of deviations between experimental and intensity of the measured VOA spectrum with the corresponding calculated data. In liquid phase, solute – solvent interactions play density functional theory (DFT) calculated VOA spectrum of a an important role in the conformer geometry and population of chosen configuration. It is important to mention that the choice of flexible molecules, mainly if experimental data in polar (H bond 35 the arbitrary configuration is based on the relative configuration forming) solvents need to be reproduced. In the case of rigid determined using NMR or X ray crystallography. If the major 95 molecules, solvent polarization effects may be the principal cause bands of the measured and calculated VOA spectra agree in of deviations. Thus, the inclusion of either the polarizable relative magnitude and sign, then the AC chosen for the continuum model (PCM) or the conductor like screening model calculation is the same as that of the sample measured. If the 48 (COSMO), as opposed to gas phase calculations, is preferred. 40 relative magnitudes agree, but the signs are opposite, then the AC 29 Nevertheless, in some cases, the use of explicit solvation may be of the sample is the opposite of that chosen for the calculation. 49 100 necessary for a reliable simulation. As the timescale of a vibrational transition is shorter than a ps Regarding conformational studies of biomacromolecules, the (10 −12 s), the boundary for conformational rearrangements in 21 interpretation of VOA spectra has been predominantly based on flexible molecules is reasonably low at room temperature. 50,51 empirical analysis (structure spectra correlations). In this 45 Consequently, VOA experimental spectra are composed of the case, the comparison of similar spectral patterns of molecules of linear superpositions of the spectra of individual conformers, 42 105 known structure with those of samples of unknown conformation weighted by the corresponding conformational populations. is used to assign the structural features of the latter. This practice This fact makes it extremely important to carry out a thorough 43 allows for the identification of marker bands that are diagnostic conformational search, followed by geometry optimization, of particular structural motifs. Such empirical correlation may be 50 before calculating the chiroptical property of interest using DFT supported by statistical methods, such as principal components methods. Overlooking any significantly populated conformer 52 110 analysis. Further discussions on VOA theory, instrumentation, may result in inaccurate VOA theoretical spectra and therefore measurements and calculations are beyond the scope of this poor agreement between experimental and calculated data. review article and one can find valuable information in the The level of agreement between experimental and calculated extensive literature available.53 66 55 VOA spectra may be determined visually, which is considered to In the following sections we will present examples of the be the least reliable method, since it is prone to user bias, or by 115 application of VCD and ROA for stereochemical characterization using recently developed statistical methods. The first one
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of representative natural products. These examples will be 1R,5 R,7 S,8 S,10 R by comparison of experimental and calculated organized chronologically in different classes and subclasses of VCD data at the B3LYP/6 31+G(d,p) level. 79 The brominated secondary metabolites, such as terpenes, alkaloids, lignans, sesquiterpenes (−) majapolene B ( 20 ) and ( −) acetylmajapolene meroterpenes, coumarins and flavonoids, miscellaneous, peptides 60 B ( 21 ) isolated from the red algal genus Laurencia had their 5 and carbohydrates, regardless of the sources from which they absolute configuration determined as 7 S,10 S using VCD and DFT were isolated. calculations at the B3PW91/6 31G(d,p) level. 80 Similarly, a diastereomeric mixture on the peroxide portion of the brominated sesquiterpene acetylmajapolene A was separated and the absolute VOA and Natural Products 65 configuration of the diastereomers (−) 22 and (−) 23, which were basically indistinguishable, was assigned as 1R,4 R,7 S,10 S and Terpenes 1S,4 S,7 S,10 S, respectively. 81 Another example include the 10 Historically, chiral terpenes, especially monoterpenes, have been cytotoxic sesquiterpene quadrone ( 24 ) isolated from Aspergillus used to test VOA devices because of their availability in suitable terreus .82 The absolute configuration of (−) 24 was determined as enantiomeric purity and their high quality vibrational spectra in 70 1R,2 R,5 S,8 R,11 R by using a combination of OR, ECD, and VCD. the mid IR region. 67 Indeed, neat α pinene enantiomers remain Comparison of experimental VCD with the B3PW91/TZ2P the most widely used standards to verify calibration of VCD and calculated spectrum was considered to provide the most reliable 15 ROA instruments. Examples of experimental and calculated VCD assignment, which was in accordance with previous results and ROA for α pinene are presented in Figure 1. obtained via total synthesis. The reinvestigation of the absolute Additionally, a number of technological advancements in the 75 configuration of the iridoids plumericin ( 25 ) and isoplumericin VOA field were achieved using monoterpenes. Just to cite a few (26 ) using the same combination of chiroptical methods and examples, (+) (1 R) α pinene ( 1), ( −) (1 S) camphor ( 2) and ( −) calculations presented above also confirmed the previous 83 20 (1 S) endo borneol ( 3) were used in the first application of Fourier assignments of ( +) 25 and ( +) 26 as 1 R,5 S,8 S,9 S,10 S. In transform VCD (FT VCD) to follow changes in the percent addition, the highly cytotoxic iridoid ( −) prismatomerin ( 27), enantiomeric excess (% EE) of chiral molecules in time (real time 80 isolated from Primatomeris tetrandra , had its absolute monitoring). 68 Compound 2 and (+) (1 S) fenchone (4) were used configuration assigned as 1 R,5 S,8 S,9 S,10 S using VCD and DFT in experimental and theoretical studies of near infrared VCD. 69 calculations (B3PW91/TZ2P) of its acetate derivative in order to 84,85 25 Other monoterpenes whose VCD spectra were investigated in avoid aggregation. Interestingly, the signs of the OR of 25 both mid IR and near IR regions include ( +) (R) limonene ( 5), and 27 are opposite despite their identical absolute configuration, (−) (R) carvone ( 6) and its antipode ( 7), ( +) (R) pulegone ( 8), 85 that points out the risks of relying on the comparison of OR (−) (1 S) β pinene ( 9), and both enantiomers of menthol ( 10 and values for assigning absolute configurations. Experimental and 11). 70 72 The enantiomers of camphor were also employed to theoretical [B3LYP/6 31G(d,p)] VCD studies of a new 30 investigate in detail the phenomenon of induced solvent chirality eudesmanolide type sesquiterpene ( 28 ) isolated from Mikania as probed by VCD. 73 The S enantiomer of compound 1 along campanulata led to the assignment of its absolute configuration 86 with compound 5 were used in the first mid IR observation of 90 as (+) (1S,4 S,5 S,6 S,7 S,10 R). Good agreement between vibrational optical rotatory dispersion. 74 Regarding ROA, experimental VCD and the spectra calculated at the B3LYP/6 compound 1 was used in the first simultaneous acquisition of all 31G(d,p) and B3LYP/DGDZVP levels confirmed the absolute 75 35 four forms of circular polarization ROA. Finally, chiral configuration of the diterpene ( +) verticilla 3E,7 E dien 12 ol limonenes were used in the development of the femtosecond (29 ), isolated from Bursera suntui , as 1 S,11 S,12 S.87 The 76 characterization of VOA of chiral molecules. 95 eremophilanoids 6 hydroxyeuryopsin (30 ), isolated from Senecio Based on what was described above, an increasing number of toluccanus , and compound 31 isolated from Psacalium papers have been published describing the use of VCD and/or paucicapitatum had their absolute configuration determined as 40 ROA to determine conformations and the absolute configuration 4S,5 R,6 S and 1 S,4 S,5 R,8 S,10 S, respectively, by VCD and DFT of terpene molecules. calculations. VCD measurements were also carried out for the The first example is the VCD determination of the absolute 100 acetylated derivative of 30 in order to avoid intermolecular configuration of bisabolene type sesquiterpenes isolated from the hydrogen bonding of the hydroxyl group and thus improve the marine sponge Didiscus aceratus .77 The atropisomeric dimers agreement with calculated data (B3PW91/DGDZVP).88 45 (+) dicurcuphenol B ( 12 ) and (+) dicurcuphenol C (13 ) had their Salvileucalin B (32), presenting an unprecedented rearranged axial chirality assigned as P and M, respectively, while the neoclerodane skeleton, was isolated from Salvia leucantha along absolute configurations at C 7 and C 7' were determined as S by 105 with salvileucalin A ( 33). Their relative configurations were comparing experimental and B3LYP/6 31G(d) calculated data. determined by X ray crystallographic analysis and their absolute This was the first application of VCD to the stereochemical configurations (as shown in Figure 3) were assigned using VCD 89 50 analysis of marine natural products. The derivatization of ( +) and DFT [B3LYP/6 31G(d)] calculations. The africanane (1 R) endo borneol ( 14 ) to form derivatives 15 18 was used to sesquiterpene ( +) 34 isolated from Lippia integrifolia had its demonstrate that conformational rigidification of chiral molecules 110 absolute configuration assigned as 4 R,9 R,10 R using VCD and facilitates the determination of their absolute configuration using DFT calculations at the B3LYP/6 31G(d), B3LYP/DGDZVP, VCD. 78 The absolute configuration of the guaianolide 7,10 and B3PW91/DGDZVP2 levels. The lippifoliane sesquiterpene 55 epoxy 1,5 guaia 3,11 dien 8,12 olide isolated (19 ) from the 35, isolated from the same species, had its absolute configuration leaves of Hedyosmum arborescens was determined as confirmed as 4 R,9 S,10 R using the same VCD protocol. 90
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Figure 1. (Left) Comparison of observed IR and VCD spectra calculations for both diastereomers possible at C 8. This of ( −) (α) pinene with those calculated for ( S) (α) pinene using DFT approach clearly indicated that compound 40 possesses the methods; (Right) Comparison of observed Raman and SCP ROA spectra 96 35 2R,5 R,5a R,8 R,9a S configuration. Phytochemical studies in of ( −) (α) pinene with those calculated for ( S) (α) pinene using DFT Stevia monardifolia afforded the new compound 7β angeloyloxy 5 methods. These comparisons unambiguously establish the absolute configuration of ( −) (α) pinene as S. 8α isovaleroyloxylongipin 2 en 1 one. Its absolute configuration was assigned as 4 S,5 S,7 S,8 S,10 R,11 R by VCD measurements in comparison to calculations at the B3LYP/DGDZVP level. 97 The The following example deals with stereochemical studies on (+) 40 enantiomers of 3 oxo 1,8 cineole were synthesized and their (E) junionone ( 36), a monoterpene isolated from Juniperus absolute configurations were determined as ( −) (1 S,4 S) 41 and 10 communis . This is one of the few examples of the use of ROA consequently ( +) (1 R,4 R) using VCD and DFT calculations spectroscopy to assign the absolute configuration of natural (B3LYP/DGDZVP).98 The conformational landscapes of products. 91 The naturally occurring ( +) (E) 36 was assigned as R. compounds 5,67 7,99 and ( −) (S) limonene oxide ( 42), 100 a The absolute configuration of another monoterpene molecule, 45 secondary metabolite and atmospheric pollutant, were probed by (+) pulegone ( 8), was confirmed as R by comparison of VCD and quantum chemical calculations. These works also 15 experimental and calculated [B3LYP/6 311+G(d,p)] VCD reveal that IR, Raman, and VCD are helpful complementary spectra. 92 This work points out the importance of taking solvent techniques for characterizing flexible systems. Another effects into account in the calculations by using a continuum monoterpene whose absolute configuration was assigned using model. A thorough conformational analysis of the baccatin III 50 VCD and DFT calculations is ( −) myrtenal ( 43 ). Compound 43 ring ( 37) of paclitaxel using experimental and calculated VCD was assigned as 1R and the authors indicated B3LYP/DGDZVP 20 provided further insights on the conformational changes induced calculations as providing a superior balance between computer in paclitaxel upon binding with β tubulin. 93 Conformational cost and VCD spectral accuracy. 101 The same level of theory flexibility of ( S) (−) perillaldehyde ( 38), a secondary metabolite described above was used in VCD spectral calculations to and atmospheric pollutant, was also investigated using 55 confirm the absolute configuration of the longipinene derivative experimental and theoretical VCD. 94 The diterpene ( +) 7,9 diacetyloxylongipin 2 en 1 one ( 44) as 102 25 aframodial ( 39), isolated from Aframonum latifolium , and its 4R,5 S,7 R,9 R,10 R,11 R. The structure of the sesquiterpene (−) diastereomers were subjected to a theoretical VCD study that epi presilphiperfolan 1 ol isolated from Anemia tomentosa was demonstrated this VOA technique to be very sensitive not only to reassigned to ( −) 9 epi presilphiperfolan 1 ol ( 45) and its the local stereochemistry of each chiral center, but also to the 60 absolute configuration was established as 1 S,4 S,7 R,8 R,9 S using helicity of the entire molecules. 95 VCD spectroscopy and DFT (B3LYP/DGDZVP) calculations. 103 30 Even though chiroptical methods are ideally used to tell apart The structure and absolute configuration of ginkgolide B (45 ) enantiomers, the absolute configuration of the pacifenol were characterized directly in solution using experimental and derivative ( −) (40 ) was determined using VCD measurements and calculated [B3LYP/6 31G(d)] VCD. 104 Differences between
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measured and calculated IR and VCD spectra for 46 were VCD and DFT (B3LYP/DGDZVP) calculations. 116 This rationalized in terms of interactions with solvent as well as 60 molecule was assigned as intermolecular interactions. Theoretical calculations were also 5S,7 S,8 R,9 R,10 S,17 S,5 'S,7 'S,8'R,9 'R,10 'S,17 'S. The absolute performed for ginkgolides A ( 47 ), C ( 48), J ( 49) and M ( 50 ). The configuration of the rare isoneoamphilectane carbon skeleton, 5 absolute configurations of two groups of diterpenes belonging to present in marine diterpenes isolated from the sponge Svenzea opposite enantiomeric series, isolated from Chromolaena flava , was determined using VCD and DFT [B3LYP/6 31G(d)] 117 pulchella , were determined as (5 S,8 R,9 S,10 R) (−) hautriwaic acid 65 calculations. Semisynthetic derivative ( +) 68 was assigned as lactone ( 51) and (5 S,8 R,9 R,10 S) (+) isoabienol ( 52) using VCD 3S,4 R,7 S,8 S,11 R,12 S,13 R. VCD spectroscopy in combination and DFT (B3LYP/DGDZVP) calculations. 105 These results with DFT calculations (B3PW91/DGDZVP) was able to reliably 10 supported the biogenetic proposal to diterpenes in the studied discriminate four diastereomeric cedrol related tricyclic species. The new serrulatane type diterpene (−) leubethanol ( 53), sesquitepenes: cedranol (69), neoisocedranol (70 ), neocedranol 118 isolated from Leucophyllum frutescensi, had its absolute 70 (71), and isocedranol ( 72). The absolute configurations of their configuration determined as 1R,4 S,11 S after comparison of acetate derivatives were determined as (3 R,3a R,5 R,6 R,7 S,8a S) experimental VCD with B3LYP/DGDZVP calculations for both (−) 69, (3 R,3a R,5 R,6 S,7 S,8a S) (−) 70 , (3 R,3a R,5 S,6 R,7 S,8a S) 106 15 C 11 diastereomers of 53. The absolute configuration of seco (−) 71, and (3 R,3a R,5 S,6 S,7 S,8a S) (+) 72. The presence of 13 R oxacassane diterpenes was determined for the first time by and 13 S labdane diterpenes coexisting in Ageratina jocotepecana comparing the experimental VCD of the conformationally 75 was demonstrated using VCD and DFT (B3LYP/DGDZVP) restricted derivative 54 with B3PW91/DGDZVP2 calculated calculations. 119 A VCD study on ( −) 73 and (+) 74 established spectra. 107 Compound (−) 54 was assigned as 5 S,8 R,9 R,10 S. The their absolute configurations as 5 S,9 S,10 S,13 S and 20 chiral recognition of the tricyclic sesquiterpenes ( +) 6R cedrol 5S,8 R,9 R,10 S,13 R, respectively. The absolute configuration of (55) and ( −) 6S isocedrol ( 56) was successfully achieved using the diterpene (+) shortolide A (75), isolated from the endangered VCD spectrosocopy. Calculations of the anisotropy factor ( g) 80 species Solidago shortii , was determined as provided the regions of maximum VCD effect for each epimer. 108 3R,4 S,5 R,7 S,8 S,9 S,10 S using VCD and DFT [B3LYP/6 Conformational analysis of the sesquiterpene benzoquinones ( R) 311+G(2d,p)] calculations, as the crystal structure obtained for 75 120 25 perezone ( 57) and ( R) dihydroperezone ( 58) using VCD and DFT did not allow for such assignment. The rare sesquiterpene ( +) (B3LYP/DGDZVP) calculations suggested analogous 3 ishwarone ( 76), isolated from Peperomia scandens , had its conformations for both molecules and confronted previous 85 absolute configuration determined by a combination of reports on the presence of weak π π interactions between the chiroptical methods and theoretical predictions for different alkyl chain double bond and the quinone ring in 57.109 The diastereomers. 121 The best results were obtained using VCD and 30 relative stereochemistry at C 13 and the absolute configuration of vibrational dissymmetric factor spectra that led to the assignment the ent labdane salvic acid ( 59), isolated from Eupatorium salvia , of 76 as 1 R,2 S,4 S,5 R,9 R,11 R. The diterpenoid demalonyl was determined as 13 R using VCD and DFT (B3LYP/DGDZVP) 90 thyrsiflorin A acetate ( 77), isolated from Calceolaria species, was calculations of an O methyl ether methyl ester derivative. 110 The determined as belonging to the normal enantiomeric series of absolute configuration of ( +) (R) 5 and its antipode, as well as diterpenes by VCD and DFT (B3LYP/DGDZVP) calculations. 35 that of (+) (E) αl (60 ) were determined using This result, which was supported by single crystal X ray ROA spectrosocopy.111 The lupane triterpenoid epoxylupenone diffraction, was used to assign the stereochemistry of related 122 (61), prepared from lupeol, had its 20 (S) absolute configuration 95 molecules. Finally, the diastereoselectivity of diazomethane determined by comparison of observed and calculated addition to the conjugated double bond of unsaturated (B3LYP/DGDZVP) spectra. 112 Once again, VCD analysis was sesquiterpene lactones was explored using zaluzanin A, for which 40 able to distinguish between two possible epimers of a natural the absolute configuration was secured using VCD product. spectroscopy. 123 The revised structure of ( +) rosmaridiphenol ( 62), an 100 antioxidant isolated from Rosmarinus officinalis , had its absolute Alkaloids configuration determined as 5 S,10 R using VCD and DFT 113 45 calculations of its diacetate derivative. The absolute The second class of secondary metabolites with most reports on configuration of the unusual diepoxyguaianolide ( −) 63, isolated the use of VOA for stereochemical characterization is alkaloids. from Stevia tomentosa , was determined as The alkaloid (6R,7 S,9 S,11 S) (−) spateine ( 78) was used in the 1S,3 S,4 S,5 R,7 R,8 R,11 S by VCD in combination with DFT 105 first ab initio VCD calculation for a molecule containing a (B3LYP/DGDZVP) calculations. 114 This assignment was closed shell transition metal. The same molecule was also used to 50 supported by X ray crystallography. The cassane diterpenes (−) report a new VCD enhancement mechanism in open shell Co(II) 6 acetoxyvoucapane ( 64), (−) hydroxyvoucapane ( 65), and (+) 6 and Ni(II) complexes. 124 The solution state conformation of (−) oxovoucapane ( 66), isolated from Caesalpinia platyloba , had cinchonidine (79), used as a chiral modifier, was studied using 125 their absolute configurations assigned as (5 S,6 R,8 S,9 S,10 R,14 R) 110 VCD and theoretical calculations [B3LYP/6 31G(d)]. The 64, (5 S,6 R,8 S,9 S,10 R,14 R) 65 and (5 S,8 S,9 S,10 R,14 R) 66 using same work also reported the investigation of induced VCD 115 55 VCD and DFT (B3LYP/DGDZVP) calculations. Preferred activity in achiral trifluoroacetic acid upon interaction with 79 conformations and the absolute configuration of the and ( +) cinchonine (80 ). The absolute configuration at C 21 unprecedented macrocyclic dimeric diterpene ( −) schaffnerine bearing an epoxide ring on citranidin A ( 81), a pentacyclic (67), isolated from Acacia schaffneri , were determined using 115 indolinone alkaloid isolated from Penicillium citrinum , was assigned as S by comparison of the observed VCD spectrum with
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those of model compounds. 126 The absolute stereochemistry of the pentacyclic core was assigned using NMR and ECD. Two natural diastereoisomers of 6 β hydroxyhyoscyamine ( +) 82 and (−) 83 had their absolute configurations assigned as 3 R,6 R,2 'S 5 and 3 S,6 S,2 'S, respectively, using VCD and DFT [B3LYP/6 31G(d)] calculations. 127 It was also possible to observe that the lowest energy conformers in both cases showed the N Me group in the syn orientation. The absolute configuration of ( +) schizozygine (84), isolated from Schizozygia caffaeoides , was 10 determined as 2 R,7 S,20 S,21 S using a concerted application of DFT calculations of VCD, ECD and OR. 128 The related alkaloids (+) schizogaline ( 85), ( −) schizogamine ( 86), and 6,7 dehydro 19 β hydroxychizozygine ( 87), isolated from the same species, had their absolute configurations defined by that of 84 assuming a 15 common biosynthetic pathway. A second example of concerted application of chiroptical methods to assign absolute configuration on natural products included the alkaloids isochizagaline (88) and isochizogamine (89). The naturally occurring ( −) 88 and ( −) 89 were determined definitively to be 129 20 2R,7 R,20 S,21 S. In the case of actinophyllic acid, isolated from Alstonia actinophylla , VCD could not be used for stereochemical bands characteristic of these configurations observed in 135 analysis since this compound had limited solubility in 60 previously studied tropanediol derivatives. The absolute
noncoordinating solvents such as CCl 4 and CDCl 3. The configuration of the dextrorotatory aspidospermatan type measurement using DMSO d6, a strongly coordinating solvent indoline alkaloid ( 99), isolated from Geissospermum reticulatum , 25 exhibited discrepancies with calculated data. Therefore, ECD was was determined as 2 R,7 R,15 R,17 S,19 S by VCD spectrosocopy recorded in methanol and the molecule was assigned as and DFT (B3LYP/DGDZVP) calculations. 136 This assignment 130 15 R,16 S,19 S,20 S,21 R. The unexpected montanine type 65 facilitated the deduction of the absolute stereochemistry of alkaloid ( 90 ), obtained as a rearrangement product of structurally related alkaloids isolated from this plant. The fungal haemanthanine type alkaloids in the presence of halogenating secondary metabolite ( +) caripyrin (100 ), first described from 30 agents, had its absolute configuration assigned as 2 S,3 S,4a S,11 S Caripia montagnei , had its absolute configuration determined as using VCD and DFT (B3PW91/DGDZVP) calculations. 131 The R,R using VCD and DFT [B3LYP/6 311G(d,p)] calculations. 137 absolute configuration of the tropane alkaloids 6 β hydroxy 3α 70 Finally, the absolute configuration of ( −) cataubine E ( 101), senecioyloxytropane ( 91), 3 α hydroxy 6β tigloyloxytropane isolated from Erythroxylum hypericifolium , was established as (92), 3α hydroxy 6β senecioyloxytropane ( 93), and 3 α hydroxy 3R,6 R by correlation with a synthetic sample, whose 138 35 6β angeloyloxytropane (94), isolated from Schizanthus species, configuration was secured using VCD. was determined as 1 R,3 R,5 S,6 R. VCD and DFT (B3LYP/DGDZVP) calculations were compared for a pure 75 Lignans sample of 91, as well as for a 69:31 mixture of 92 and 93, and for a 7:3 mixture of 91 and 94.132 The semisynthetic ( −) 3α,6 β The first compound of this class investigated using VCD and 40 acetoxytropane ( 95), prepared from 83, had its absolute DFT calculations was the norlignan (+) nyasol ( 101 ), reported configuration determined as 3 S,6 S by comparison of experimental from Asparagus africans . Compound 102, which is among the and calculated (B3LYP/DGDZVP) VCD spectra. 133 The most flexible small organic molecules studied by VCD orientation of the N Me group was found to be predominantly 80 spectroscopy, was assigned as S after comparison of observed equatorial. The absolute configuration of the highly flexible VCD, both in solution and KBr pellets, with calculated 139 45 marine antibiotic (+) synoxazolidinone A ( 96), isolated from (B3LYP/aug cc pVDZ) data. This result enabled the Synoicum pulmonaria , was assigned as 6 Z,10 S,11 R using ECD, establishment of the absolute configuration of ( −) hinokiresinol VCD and ROA spectroscopies in combination with theoretical (103) also as S. The absolute configurations of podophyllotoxin 134 calculations for the eight possible stereoisomers of 96. ROA 85 related lignans isolated from Bursera fagaroides were determined allowed for a reliable determination of the configuration at the using VCD. Initially, the absolute configuration of ( −) 50 double bond, while VCD was necessary to resolve the chlorine podophyllotoxin ( 104) and ( −) deoxypodophyllotoxin ( 105) was substituted stereogenic center. VCD was also used to assign the assigned as 7 R,7 'R,8 R,8 'R and 7 'R,8 R,8 'R, respectively, by absolute configuration of a derivative of 96, 97 with three comparison of experimental VCD and B3LYP/DGDZVP stereogenic centers as 6 Z,10 S,11 R. VOA methods were found to 90 predicted spectra. Then, VCD measurements of (−) morelensin be more reliable than ECD. 134 Both enantiomers of 3 α,6 β (106), ( −) yatein ( 107), and ( −) 5' desmethoxyyatein ( 108) led to 55 dibenzoyloxytropane were prepared from optically active 6 β their assignments as (7 'R,8 R,8 'R) 106, (8 R,8 'R) 107, and hydroxyhyoscyamines and their absolute configurations were (8 R,8 'R) 108.140 The absolute configuration and solution state determined as ( +) (3 S,6 S) 98, and consequently ( −) (3 R,6 R), conformers of three peperomin type secolignans isolated from using VCD spectroscopy. The experimental spectra showed 95 Peperomia blanda were unambiguously determined by using VCD spectroscopy associated with DFT calculations. 141
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Compound ( −) 109 was confirmed as 2R,3 S, the same configuration assigned previously using ECD spectroscopy. 142 Peperomin B ( 110 ) was assigned as (+) (2 S,3 S,5 S) 110 by comparing observed and calculated [B3LYP/6 31G(d)] data. The 5 novel compound ( −) 111 was determined as 2 R,3 S,5 S with the aid of calculations at the B3PW91/TZVP level. ECD was not able to distinguish possible C 5 epimers for 110 and 111.141 Several dimeric stilbene glucosides were isolated from Gnetum africanum and had their absolute configurations assigned using VCD and 143 10 DFT [B3PW91/6 31G(d,p)] calculations. The two diastereomers of ( −) gnemonoside A were assigned as (7a R,8a R) and (7a S,8a S) 112. Compounds ( −) gnemonoside C ( 113) and (−) gnemonoside D (114) were assigned as 7a S,8a S. The two enantiomers of gnetin C, obtained from the aglycones of 112 and 15 its diastereomer, were assigned as ( −) (7a S,8a S) 115 and ( +) (7a R,8a R). Finally, the bioactive compound ( +) schizandrin (116), isolated from Schisandra sphenanthera , had its absolute configuration reassigned using VCD and DFT [B3LYP/6 311+G(d)] calculations for two the diastereomers possible. 144 The 20 configuration of ( +) 116 was unambiguously established as 7 S,8 R and not 7 S,8 S as previously reported.
Meroterpenes Meroterpenes are another class of secondary metabolites 25 commonly studied using VOA spectroscopic methods. Novofumigatonin ( 117), a new orthoester meroterpenoid isolated from Aspergillus novofumigatus had its relative stereogeometry established by NMR and X ray analysis. However the determination of its absolute configuration (as depicted below), 30 was only possible by using VCD and DFT [B3LYP/6 31G(d,p)] calculations. 145 The absolute configuration of ( −) stypotriol ( 118) isolated from Stypodium zonale was determined as 3S,5 R,8 R,9 R,10 S,13 S,14 S using VCD and B3LYP/DGDZVP predicted spectra for the triacetate derivative. This derivative was 35 considered the largest natural product molecule studied by VCD at that time.146 Recently, larger molecules have been successfully studied using this technique, and an example has been published (see compound 67). The meroditerpenoid isoepitaondiol ( 119), isolated from Stypopodium flabelliforme, had its structure 40 reassigned based on NMR and X ray diffraction data. The absolute configuration of the revised structure (as depicted below) was determined using VCD and DFT (B3LYP/DGDZVP) calculations for the diacetate derivative. 147 The absolute configuration of two prenylated chromanes from Peperomia 45 obtusifolia , ( +) peperobtusin A ( 120 ) and ( +) 121 , was reassigned as R using VCD and DFT [B3LYP/6 31G(d)] calculations. 148 The previous erroneous assignments were based on the ECD helicity rule for the chromane chromophore, 149 which was shown to be invalid for the title molecules after theoretical calculations of 50 ECD spectra. Sargaol acetate ( 122), a chromene substituted with a large unsaturated carbon chain isolated from Stypopodium flabelliforme , had its absolute configuration determined as ( +) (R) using VCD and DFT (B3LYP/DGDZVP) calculations. 150 The absolute configuration of a dextrorotatory benzodihydrofuran 55 (123) isolated from Cyperus teneriffae was determined as S by comparison of observed and B3LYP/DGDZVP calculated data. 151 The prenylated chromene gaudichaudianinc acid ( 124), the major metabolite from Piper gaudichaudianum , was isolated as a
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racemic mixture and the absolute configuration of its enantiomers compounds exhibiting mixed biosynthetic origins. The first was determined as ( −) (R) 124 and consequently ( +) (S), by example is the polyphenolic binaphthyl dialdehyde gossypol means of a combination of ECD and VCD spectroscopy using 60 (140 ), which presents axial chirality. The excellent agreement DFT calculations. 152 Six novel monoterpene chromane esters between experimental VCD and intensity calculations carried out 5 were isolated from Peperomia obtusifolia and their absolute at DFT [B3LYP/6 31G(d)] level established the absolute configurations, which could not be assessed using any standard configuration of ( −) 139 as M.161 A series of phytoalexins have classical technique, were determined using VCD and DFT also been studied using VCD spectrosocopy. The absolute [B3LYP/6 31G(d)] calculations. The molecules ( −) 125, ( +) 126, 65 configuration of the naturally occurring ( −) dioxibrassinin ( 141) (−) 127, and ( +) 128, were elucidated as both enantiomers of 121 and ( −) 3 cyanomethyl 3 hydroxyoxindole ( 142), first isolated 10 esterified with the enantiomers of 3, while compounds ( −) 129 from Pseudomonas cichorii inoculated cabbage ( Brassica and ( +) 130 were characterized as both enantiomers of 121 oleracea ), was determined as S by VCD and DFT [B3LYP/6 esterified with (+) (1 R) endo fenchol. Arithmetical operations of 31G(d,p)] calculations performed for semisynthetic samples. 162 experimental and calculated spectra led to the identification of 70 The other cruciferous phytoalexins (+) 1 methoxyspirobrassinin VCD spectral signatures for the monoterpene and the chromane (143) and (−) methoxyspirobrassinol methyl ether ( 144) had their 153 15 moieties. The structure of filifolinol acetate (131) was absolute configurations determined as R and 2 R,3 R, respectively, reassigned using NMR and single crystal X ray analysis, and its by comparison of observed VCD and B3LYP/6 31G(d,p) absolute configuration was determined as 2 S,9 S,12 R using VCD calculated spectra. 163 These assignments were also supported by 154 and DFT (B3LYP/DGDZVP) calculations. The absolute 75 ECD analysis. The absolute configuration of ( −) brassicanal C configuration of the algal meroditerpenoids ( −) taondiol diacetate (145), which was also isolated from cabbage inoculated with P. 20 (132) and ( +) epitaondiol diacetate (133) was determined by cichorii , was determined as S by using a combination of OR, VCD and DFT calculations (B3LYP/DGDZVP and ECD, VCD along with DFT predicted spectra. 164 B3LYP/DGDZVP2, respectively). Compound 132 was assigned Many chromones and furanones have also been investigated as 2 S,3 S,6 R,7 R,10 R,11 R,14 S while 133 was determined as 80 using VOA methods. The dihydrofurochromones ( +) 146, ( +) 2S,3 S,6 S,7 S,10 R,11 R,14 S.155 A new diasteromeric mixture (134) 147 had their absolute configuration assigned as S by chemical 25 containing the enantiomers of 129 and 130 was isolated from correlation with ( +) 5 O methylvisamminol ( 148), whose Peperomia obtusifolia .156 VCD analysis, which was carried out absolute stereochemistry was established as S by VCD without the aid of DFT calculations, allowed the assignment of spectroscopy and DFT (B3LYP/DGDZVP) calculations. 165 The the putative compounds as a racemic mixture of the chiral 85 new visamminol derivative ( +) 4' angeloylvisamminol ( 149 ), chromane 121 esterified with the monoterpene (1 S,2 S,4 R) isolated from Arracacia tolucensis , had its structure and absolute 30 fenchol. Zonaquinone acetate (135), isolated from Stypopodium configuration determined using VCD and DFT zonale , had its absolute stereochemistry assessed by VCD (B3LYP/DGDZVP) calculations. Compound ( +) 149 was measurements and DFT (B3LYP/DGDZVP) calculations. assigned as S.166 The absolute configuration of the new Compound ( +) 135 was confidently assigned as 90 metabolite ( +) microsphaeropsone A ( 150 ), isolated from 2R,3 R,6 R,7 R,10 R,11 R,14 S.157 Finally, the absolute configurations Microsphaeropsis species, was safely determined as 1 R,2 R by 35 of spiroindicumides A ( 136) and B ( 137), isolated from comparison of ECD and VCD spectra with theoretical Chaetomium indicum , were determined as 2 'R,6 S,7 S and calculations of both properties. 167 The natural product ( +) 2'R,6 S,7 R, respectively, by the VCD exciton chirality method oxalicumone C ( 151) was synthesized and had its absolute 158 using only ca. 0.3 mg of each sample. 95 configuration determined as S using a combination of experimental and calculated ECD and VCD data. In order to improve the agreement between experimental and B3LYP/6 40 Coumarins and Flavonoids 311G(d,p) calculated VCD, the two hydroxyl groups of 151 were Despite their wide occurrence in nature, there is only one silylated to avoid hydrogen bonding interactions. 168 The odorous example of the use of VOA for stereochemical characterization of 100 2 substituted 3(2 H) furanones (+) 152 and (+) 153 had their a coumarin and one of a flavonoid. The dihydrofuranocoumarin absolute configurations determined for the first time as R by (+) alternamin ( 138), isolated from Murraya alternans , had its using VCD in combination with B3PW91/6 31G(d,p) calculated 45 structure and absolute configurations determined as ( S) 5,8 spectra. VCD measurements on the corresponding alcohol
dimethoxymarmesin using VCD and DFT (B3PW91/6 molecule were hampered by its immediate racemization in CCl 4, 159 169 311++G(d,p) calculations. The flavanone naringenin ( 139) had 105 CDCl 3, and CD 2Cl 2. The absolute configuration of two its configurational and conformational properties assessed by tautomers of homofuraneol ( +) 154 and ( +) 155, with unique VCD and DFT (B3PW91/TZ2P) calculations. The R keto enol structures, was determined as R by direct measurement 50 configuration was assigned to the enantiomer exhibiting ( +) of the VCD spectra of their methyl ether derivatives compared optical rotation. Once again VOA was found to be superior to with B3PW91/6 31(d,p) calculations. 170 The chiral furanones ( −) ECD in monitoring conformational changes in chiral 110 sotolon ( 156) and ( +) maple furanone ( 157) had their absolute molecules. 160 configurations assigned as R by comparing VCD experimental spectra with B3PW91/6 31G(d,p) calculated ones. Interestingly, these two compounds present opposite signs of optical rotation, 55 Miscellaneous despite their striking structural similarity and identical absolute 171 VOA methods have also been successfully applied to determine 115 configuration. Klaivanolide (158), an antiparasitic compound the solution state conformation and absolute configuration of
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isolated from Uvaria klaineana , was originally assigned as a seven membered lactone whose absolute configuration was determined as ( +) (S) using VCD and DFT (B3LYP/TZ2P). 172 However, the attempt to synthesize 158 led to the complete 5 reinterpretation of its originally assigned structure. Klaivanolide is actually the known molecule acetylmelodorinol ( 159). VCD calculations [B3LYP/6 31G(d)] on the reassigned structure confirmed the absolute configuration at C7 as S.173 The absolute configuration of (+) cephalochromin ( 160 ), a homodimeric 10 naphthpyranone containing both axial and central chirality was determined as a S,2 R,2 'R using a combination of OR, ECD, and effects. 182 A series of dioxolanone type secondary metabolites VCD in conjunction with the corresponding quantum chemical 60 from Guignardia bidwelli had their absolute configurations predictions at the B3LYP/6 311G(d) level. VCD was found to be assigned using VCD and ECD spectroscopies. VCD was the only method capable of determining simultaneously the considered to be superior to ECD for the determination of 174 15 configuration of both chirality elements. Comparison of absolute configurations of these compounds exhibiting central theoretical (B3PW91/TZ2P) and experimental VCD spectra of a chirality. 183 Pheguignardic acid ( 171 ), alaguignardic acid ( 172), synthetic sample of the obscure mealybug sex pheromone (+) 161 65 guignardianone A ( 173), guignardianone B ( 174), guignardianone allowed the determination of the absolute configuration of the C ( 175), and guignardianone D ( 176) were assigned as S by insect’s pheromone as 1 S,2 S,3 R.175 The absolute configuration of comparison of experimental VCD and B3LYP/6 311G(d,p) 20 the fungal metabolite hexylitaconic acid ( 162), a structurally predicted spectra. As for 171 and 172, methyl ester derivatives unique methylenesuccinic acid, was determined as ( −) (R)/( +) (S) were prepared in order to improve the agreement with theoretical using VCD and DFT [B3LYP/6 311++G(d,p)] calculations for 70 data. Teraspiridoles A ( 177) and B ( 178), formed from the merger methyl ester and lactone derivatives. 176 Aeroplysinin 1 ( 163), an of a diterpene and modified indole scaffold, were isolated from antiangiogenic drug extracted from Aplysina cavernicola , had its Aspergillus terreus and had their absolute configurations assigned 25 conformational properties in aqueous solution and absolute as ( +) (5 R,7 S,8 R,9 R,10 R,13 S,14 S,16 S,22 S,23 S) 177 and (+) configuration determined using ROA and DFT (B3LYP/aug cc (5 R,7 S,8 R,9 R,10 R,13 S,14 S,16 S,22 S) 178 by using a combination pVDZ) calculations. The calculations were performed for the four 75 of ECD and VCD experiments and calculations [B3LYP/6 stereoisomers possible, which resulted in the assignment of 163 31+G(d,p)].184 The absolute configuration of the thymol as 1 S,6 R.177 VCD in the solid state was also investigated showing derivative ( +) 179, isolated from Ageratina cylindrical , was 30 a nice example of the complementarity of both techniques in established as S using X ray analysis as well as VCD in different conditions. The great importance of including solvent combination with DFT calculations. In this case, the functional effects in quantum chemical calculations of OR, ECD and VCD 80 PBEPBE was found to provide a better agreement between was demonstrated using ( +) (2 S,3 S) garcinia acid dimethyl ester experimental and calculated data at a lower computational cost. 185 (164). 178 (+) Crassipin C ( 165), a new terpenylated Naphtoquinones have also been investigated using VOA 35 acylphoroglucinol isolated from Elaphoglossum crassipes , had its methods. The rare derivatives of dehydroiso α lapachone ( −) 180 absolute configuration at C 4 determined as R by ECD, VCD, and and ( −) 181 , isolated from Heterophragma adenophyllum , had theoretical calculations. However, comparison of experimental 85 their relative and absolute configurations reassigned using NMR and calculated VCD at the B3LYP/6 31G(d) level could not Mosher’s method, X ray analysis, and VCD combined with DFT confidently establish the absolute configuration at C 2'.179 The [B3LYP/6 311++G(d,p)] calculations. The relative orientation of 40 formation of aggregates and/or solute solvent complexes in chiral the isopropenyl and OH groups of 180 and 181 was revised to natural products occurring as carboxylic acids makes the use of trans and the absolute configuration at C 3 was assigned as S.186 chiroptical methods more challenging. In order to avoid 90 The absolute configuration of a new S bridged aggregations, the use of the corresponding sodium salts or acid pyranonaphytoquinone dimer, isolated from Nonomuraea specus , anhydrides was proposed. The effects of this approach on VCD, was determined by comparing experimental and calculated OR, 45 ECD and OR properties were evaluated using the acid form of ECD, and VCD for the monomeric congener hypogeamicin B 164 and ( +) (2 S,3 R) hibiscus acid ( 166). 180 The uncommon (182). Compound ( −) 182 was assigned as 1 R,3 S,4a S,10a R. compound (−) preussidone ( 167), obtained from Preussia 95 Accordingly, on the basis of the likely conservation of epoxide typharum , had its absolute configuration unambiguously assigned ring opening stereo and regiochemistry, the dimer was proposed as R using quantum chemical ECD and VCD calculations. 181 The to have 1 R,3 R,4a R,10a S,10 R,3 'R ,4a 'R,10a 'S.187 50 absolute configurations of ( −) phyllostin ( 168), ( −) scytolide Finally, the relative configuration of a key subunit of (169), isolated from Phyllosticta cirsii , and ( +) oxysporone ( 170 ), hemicalide, isolated from Hemimycale sp., was established by isolated from Diplodia africana , were determined by 100 combining stereocontrolled synthesis of model substrates, with computational analysis of their ORD, ECD, and VCD spectra. NMR and VCD spectroscopy. The C 36 C46 unity ( 183) of Compound ( −) 168 was assigned as 3 S,4a R,8 S,8a R using the hemicalide had its configuration determined as 55 three chiroptical methods, while ( −) 169 was assigned as 36 S*,37 S*,39 S*,40 S*,42 R*,45 R* . The absolute configuration at 4a R,8 S,8a R using ECD and VCD. Satisfactory agreement C 42 of the synthetic models was secured by VCD and DFT 188 between experimental and calculated VCD for ( +) 170 , assigned 105 (B3LYP/aug cc pVDZ) calculations. as 4 S,5 R,6 R, was only obtained after taking into account solvent
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Compound 189 was found to adopt a bracelet type structure in Peptides and Carbohydrates inert solvents, while a propeller type structure was suggested in 190 Peptides and carbohydrates comprise important and varied polar solvents. The structure of the potassium complex of 189 classes of biomolecules for which the use of VCD and ROA are in solution was also investigated using ROA and theoretical 20 calculations. It was found that the most populated conformer does 5 well established. Although not the focus of this review article a not exhibit C symmetry, and is different from that present in the few examples on the use of VOA for stereochemical 3 crystal and the NMR derived strucuture. 191 Pexyganan, a 22 characterization of peptides will be presented. Cyclosporins A amino acid peptide analogous to the magainin peptides present in (184), C ( 185), D ( 186), G ( 187), and H ( 188) had their the skin of the African clawed frog, had its conformational conformational preferences in CDCl 3, as well as that of their 25 preferences in solution probed by VCD and ECD spectroscopies. 10 magnesium complexes in CD 3CN, investigated using VCD spectrosocopy. DFT calculations at B3PW91/6 31G(d) level were This peptide appears to adopt an α helical conformation in TFE, a sheet stabilized β turn structure in methanol, a random coil with used for fragments of 184 and 188 obtained from crystal 189 β turn structure in D O, and a solvated β turn structure in structure. The conformations of valinomycin ( 189) in different 2 DMSO. 192 The desulfurization of the 3,6 epidithio solvents and the influence of various cations were investigated 30 diketopiperazine metabolite chaetocin ( 190 ), isolated from 15 using VCD spectrosocopy and B3LYP/6 31G(d) calculations.
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Chaetomiun virescens , was demonstrated to take place with retention of configuration by the analysis of the desulfurized product using ECD and VCD. 193 This work was the base for the establishment of a universal mechanism for the desulfurization of 194 5 this class of compounds. Furthermore, a combination of chiroptical spectroscopic methods was successfully applied to two new dimeric epipolythiodiketopiperazines, preussiadins A (191 ) and B ( 192), obtained from the mycelia of a Preussia typharum isolate. These compounds had their absolute 195 10 configurations determined using OR, ECD, and VCD, and compound 191 was assigned as 3S,5a R,10b S,11 S,12 S,3 'R ,5a 'S ,10b 'R ,11 'S ,12 'R by comparison of its experimental and calculated [B3LYP/6 31+G(d,p)] chiroptical data. Following this assignment, the absolute configuration of 15 192 was also confirmed to be identical to that of 191 by chemical correlation. Regarding carbohydrates, VOA, especially VCD, has been extensively used to assign the configuration at the anomeric carbons in monosaccharides as well as the stereochemistry of the 20 glycosidic bonds in disaccharides. Suitable references can be found here. 196 205
Conclusions Back in 2000, 28 Allenmark stated: “This (VCD) is likely to become of great importance for the structural elucidation of 25 natural products in the future”. Almost fifteen years later, we can confirm herein that VOA methods have indeed become robust and reliable alternatives for the stereochemical characterization of natural product molecules, especially in conditions not accessible to other methods. Nevertheless, a careful look at the data 30 presented here reveals that almost 50% of all literature reports on VOA for conformational and configurational analysis of natural products come from two main research groups, that is, Pedro Joseph Nathan’s group in Mexico and that of Kenji Monde in Japan. Given the large number of researchers focused on natural 35 products all over the world, and the growing need for accurate methods to characterize the molecular structure of natural compounds, we believe that VOA has a great potential to and should become a more routinely used tool in this field worldwide. Another interesting fact is how much the use of ROA 40 spectroscopy still lags behind that of VCD. Out of all the examples given here, only 6 involved ROA. However, as more spectrometers become installed and more natural product research groups learn about the advantages of using ROA spectroscopy, this scenario is likely to change in the near future. 45
Acknowledgements We thank São Paulo Research Foundation (FAPESP) grant #2014/50304 9, 2013/07600 3 and 2011/22339 4. We also thank Dr. Andrea N. L. Batista for her invaluable help with the 50 literature search.
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Notes and references 28 S. Allenmark, Nat. Prod. Rep., 2000, 17 , 145 155. 29 L. A. Nafie, Nat. Prod. Commun. , 2008, 3, 451 446. aDepartment of Chemistry, Federal University of São Carlos – UFSCar, 30 P. J. Stephens, F. J. Devlin and J. J. Pan, Chirality , 2008, 20 , 643 Rod. Washington Luís, km 235, São Carlos, SP 13565 905, Brazil. Fax: 663. +55 (16) 3351 8350; Tel: +55 (16) 3351 8206; E mail: 75 31 P. J. Stephens and F. J. Devlin, in Encyclopedia of spectroscopy and 5 [email protected] spectrometry , ed. J. C. Lindon, G. E. Tranter and D. W. Koppenaal, bSchool of Applied Sciences, RMIT University, GPO Box 2476, Academic Press, London, 2010, pp. 2916 2937. Melbourne VIC 3001, Australia. Tel: +61(0)3 9925 2890; E mail: 32 Y. He, B. Wang, R. K. Dukor and L. A. Nafie, Appl. Spectrosc. , [email protected] 2011, 65 , 699 723. c Department of Chemistry, Institute of Chemistry, São Paulo State 80 33 P. L. Polavarapu, in Comprehensive chiroptical spectroscopy: 10 University – UNESP, R. Prof. Francisco Degni, 55, Araraquara, SP applications in stereochemical analysis of synthetic compounds, 14800 060, Brazil. Fax: +55 (16) 3322 2308; Tel: +55 (16) 3301 9660; natural products, and biomolecules , ed. N. Berova, P. L. Polavarapu, E mail: [email protected] K. Nakanishi and R. W. Wood, John Wiley and Sons, New Jersey, 2012, pp. 147 177. 85 34 P. J. Stephens, F. J. Devlin and J. R. Cheeseman, VCD spectroscopy 15 1 V. Davankov, Chirality , 2006, 18 , 459 461. for organic chemists , CRC Press, Boca Raton, 2012. 2 J. M. Finefield, D. H. Sherman, M. Kreitman and R. M. Williams, 35 J. M. Batista Jr. and V. S. Bolzani, in Studies in natural products Angew. Chem. Int. Ed. , 2012, 51 , 4802 4836. chemistry , ed. A. u. Rahman, Elsevier, Oxford, 2014, pp. 383 417. 3 N. Berova, L. Di Bari and G. Pescitelli, Chem. Soc. Rev. , 2007, 36, 36 P. Joseph Nathan and B. Gordillo Román, in Progress in the 914 931. 90 chemistry of organic natural products , ed. A. D. Kinghorn, H. Falk 20 4 P. L. Polavarapu, Chirality , 2002, 14 , 768 781. and J. Kobayashi, Springer International Publishing, 2015, pp. 311 5 J. M. Batista Jr., in Stereoselective synthesis of drugs and natural 452. products , ed. V. Andrushko and N. Andrushko, John Wiley and Sons, 37 L. D. Barron, A. D. Bogaard and A. D. Buckingham, J. Am. Chem. New York, 2013, pp. 1571 1599. Soc. , 1973, 95 , 603 605. 6 N. Harada, K. Nakanishi and N. Berova, in Comprehensive 95 38 G. Holzwarth, E. C. Hsu, H. S. Mosher, T. R. Faulkner and A. 25 chiroptical spectroscopy: applications in stereochemical analysis of Moscowitz, J. Am. Chem. Soc. , 1974, 96 , 251 252. synthetic compounds, natural products, and biomolecules , ed. N. 39 L. A. Nafie, J. C. Cheng and P. J. Stephens, J. Am. Chem. Soc. , 1975, Berova, P. L. Polavarapu, K. Nakanishi and R. W. Wood, John Wiley 97 , 3842 3843. and Sons, New Jersey, 2012, pp. 115 166. 40 Bruker, Corp., Jasco, Inc., and BioTools, Inc. offer either VCD 7 P. L. Polavarapu, Chem. Rec ., 2007, 7, 125 136. 100 accessories or stand alone instrumentation. BioTools, Inc. is to date 30 8 T. Bruhn, G. Pescitelli, S. Jurinovich, A. Schaumlöffel, F. Witterauf, the only company offering ROA spectrometers. J. Ahrens, M. Bröring and G. Bringmann, Angew. Chem. Int. Ed. , 41 The main software packages available for DFT calculations of VOA 2014, 53 , 14592 14595. spectra are: Gaussian, Dalton, and CADPAC. References for these 9 E. Giorgio, R. G. Viglione, R. Zanasi and C. Rosini, J. Am. Chem. three packages, respectively, are given below. Soc. , 2004, 126 ,12968 12976. 105 (a) M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. 35 10 P. J. Stephens, D. M. Mccann, J. R. Chesseman and M. J. Frisch, Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Chirality , 2005, 17 , S52 S64. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. 11 D. Slade, D. Ferreira and J. P. J. Marais, Phytochemistry , 2005, 66 , Izmaylov, J. Bloino, G. 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